ABSTRACT The overarching goal of the University of Chicago Medicine Comprehensive Cancer Center (UCCCC) Molecular Mechanisms of Cancer (MMC) Program is to identify and characterize molecular mechanisms underlying cancer cell growth and metastasis leading to development of improved treatment options through discovery-based science. To meet these overall objectives, the MMC Program has been organized by its leadership around three key scientific themes: 1) mechanisms of altered gene expression in cancer that encompasses understanding the significance for cancer etiology of genomic rearrangements, context-specific gene expression patterns and altered gene signatures, chromatin modifications and epigenetic marks and RNA biology; 2) mechanisms of transformation and altered cell growth in cancer, that includes analysis of how proliferation, differentiation, metabolism, cell death and autophagy are deregulated in cancers, and the role these processes play in cancer stem cells and therapy responses; and 3) mechanistic analysis of the tumor microenvironment and cancer metastasis, with an emphasis on defining novel mechanisms of altered cell motility, loss of adhesion, extra-cellular matrix control, acquisition of invasiveness, cell-cell signaling in the tumor microenvironment, tumor hypoxia, cancer-associated fibroblasts, and tumor-associated macrophages. The MMC Program consists of 37 faculty members from 14 Departments, including key faculty from the Department of Chemistry. In the current funding period (2013-2016), Program members published 564 cancer-related articles (18% intraprogrammatic, 34% interprogrammatic, and 60% interinstitutional). W2Program members are supported by $8.52 M (direct costs) in peer-reviewed funding, and $2.80 M (direct costs) from the National Cancer Institute (NCI), as well as $4.2 M (direct costs) in non-peer-reviewed funding. The focused development of MMC during the past 5 years provides the requisite infrastructure and knowledge base to forge translational research interactions within our own Cancer Center and with other Cancer Centers. A major strength of the Program over the past 5 years has been the expansion of research into mechanisms of metastasis and epigenetic signaling, as well as the new development of chemical approaches in cancer research. In summary, the MMC Program has a major impact on all components of the UCCCC as the primary driver of basic scientific discovery in molecular mechanisms of cancer using systems approaches, model organisms and primary human tumor samples. The interactions of MMC Program members with other UCCCC faculty through intra- and interprogrammatic collaborations further enable the key scientific steps needed for the discovery and development of promising therapies. Moving forward, MMC Program leadership recognizes new opportunities by leveraging our growing strengths especially in chemical biology, tumor metabolism, tumor microenvironment and immunology, and cancer metastasis, with the overarching goal of increasing successful basic science-clinical partnerships in these areas.